New n-(5-nitro-2-furfurylidene)-3-amino-2-oxazolidones



in which Fflflfi? 7 NEW N-(S-NITRO-2}FURFURYUDENE)-3-AMINO-' Z-OXAZOLIDONES Gabriel Gever, Oxford, N. Y., assignor, by mesne assignments, to The Norwich Pharmacal Company, Norwich, N. Y., a corporation of New York p Serial No.214,- 6 6 clams. '(Cl. 266-240 N 0 Drawing. Application February 28, "1952,

/O ***7\ Ri Ri ht R4 R1 is a member of'the group consisjt ingiof hydrogen,

lower alkyl, hydroxy j( lower alkyl and halogeno (lower);alkyl lower alkyl, .hydroxy (lower) alkyl and halogeno 2,742,462 Patented Apr. 17, 19 56 monella is the causative agent of typhoid fever for which no truly' successful chemotherapeutic agent has yet emerged. The V. c omma bacillus :is the causative'agent ofcholera; a disease of epidemic proportions in some 5 countries. The dosage, per os, 'necessaryto obtain a high order of chemotherapeutic protection in'animals lethally infected with these organisms is'most tolerableand pro- .v okesno manifestation ofrtoxic response. The high dierapeutic index of the members of my new sen'esiof compounds permits dosages to bewell spacedat time intervals in keeping with accepted modes. of therapy? an in'itial dosejbeing followed by further doses at determined intervals; and, in some cases, aninitial dose may serve as the only administration thereof, the samehigh order of chemotherapeutic effectiveness being derived 'fromthe single 'dose as from multiple repeated doses.

The formulation of the members of my new series of compounds in a manner which will permit oral administ-rationthereof is easy. The particular compound selected for use may be incorporated in tablets or. in 102- enges. ,jSuoh tabletsare compounded in conventional fashion 'bygranulati-ng the compound withstandardstarch paste, drying, adding dry starch and pressing -out the tablets, The lozenges arecompounded in conventional fashion also, by }granulating with sugar syrup andfthen adding bulk in the form of powdered sugar and .dry starch,

and a flavoringmaterial. V The various members of the new' series of compounds which I have invented differ from each other somewhat in degree" of chemotherapeutic effectiveness. The one which Inow'prefer and with'which :I 'have secured excellent re- Isults is N (5-nitro 2-furfurylidene;)-3-amino-2 oxazoli- R3 is a member orfinei'g'rlmi consisting of liydrogen,

lower alkyl, hydroxy flower) alkyl and halogeno (lower) alkyl R4 is a member of the group consisting of hydrogen,

lower alkyl, 'hydroxy (lower) alkyl It is known 'thatnitrofurans as a class possess antibacterial activity. Those antibacterial nitrofurans may be placed in'two groups: 1) Compounds whose use has been-limited to local administration; and.1(2) 'Componnds v 'whihalso exhibit chemotherapeuticiactivityzuponzoralad- 40 (lower) alkyl and halogeno ministration; "In the' past, the compoundsfi inzthe.second ;group-ha-ve possessed an objectionable -cl' a ra'oterist-ic.:in that, when-administered in sutiicient quantity to serve :as

elfe'c'tive -'.c hemotherap eutic agents, ?they .have frequently caused nausea and vomiting. -Tliisfha's =imposed a dis'tinct limitation upon the usenf such compounds.

I have made the surprising discovery that the series of N-(S-nitro-Z-furfiui'rylidr'reh .sfi-amino-s'teoxazolidones re- 5 ferred to above, while possessinglithe high order of antibacterial activity of past nitrofurans and the chemotherapeutic effectiveness that characterizes the group of past nitrofurans which could be administered orally, differ markedly therefrom in that they are remarkedly free from the untoward and unwanted efiects of nausea and vomiting,-

when administered 'o'rally in amount sufficient to afford protection of a high order. Their use is not attended .by the danger that the recipientof a drug made therefrom may 'be unable to retain it and allow it tojperfor'm its desired therapeutic function. v I p W The members of my new series of .compoundsjhave f prove'd, in the 'treajtmen't of animals lethally infectedfwith pathogenic organisms, .to bejpo'ssessed -or" 'curativejproper- ",tiesfof arr/astonishingly highprder: @rotectioh offthe order of"'100% "is' afiordedypo'st in ectiomftojanimals, lethally infected with S. typhosa and V. comma. $211- the members of my new series of compounds comprises condensin ga suitable S-aminoQ-oxazolidone compound with 5-nitro 2 furaldehyde, its reactive derivatives such as 5-;nitro-2 furaldehyde diacetate. 7 Other methods ofproducing my ne compounds use, as starting materials, 5-nitro-2-"furfurylidene hydrazine compounds of the formula:

in which 'Xand Y aresubstituents which are capablc,

eitherlby condensing with themselves or by reacting with other suitable compounds, offorniing an'oxazohdone ring andproducing a compound described bythe "general Qmaterials. in thepreparation 'of-mynew series of ,corn- :pounds are new, perse. Suchpompounds andtheprepara -tionthereofiorrnthe subject .ofU. S..P atent,N o. 2,652,-

?ldl'issued'on my co-pen'ding application, Serial No.,274,-

" o'er-and February 28,1952.

' "In order-that myinvention may be" entirely 'availaghle toithose skilled in the a'rt, methodsfor making a nui'nber of the new compounds of the seriesare described briefly ethylhydrazine and 90 cc. of diethyl carbonate. The resulting solution is refluxed for three hours and then cooled to room temperature. From this point, two alternative procedures can be followed to obtain the N-(-nitro-2- furfurylidene) -3-amino-2-oxazolidone.

1. To the above reaction mixture is added 375 cc. of alcohol and 25 cc. of concentrated hydrochloric acid. This solution is then added, with stirring, to a solution of 75 g. of S-nitrO-Z-furaldehyde in 750 cc. of alcohol. The resulting mixture is stirred for one hour and then filtered. The yellow solid is washed with water and then with alcohol. After drying, 107 g., 79% of N-(S- nitro-Z-furfurylidene)-3-amino-2-oxazolidone is obtained. Recrystallization from N,N-dimethylformamide yields a product with a melting point of 256-257 C.

2. To the original reaction mixture is added 40 cc. of alcohol, 240 cc. of water, 38 g. of sulfuric acid and 127 g. of 5-nitro-2-furaldehyde diacetate. This mixture is stirred at reflux for one hour, cooled to room temperature and then filtered. The yellow solid is washed with Water and then with alcohol. After drying, 103 g., 76% of N-(S-nitro-Z-furfurylidene)-3-arnino-2-oxazolidone is obtained. Recrystallization from N,N-dimethylformamide yields a product with a melting point of 256- 257 C.

B. To 100 g. of 5-nitro-2-furaldehyde 2-(2-hydroxyethyl) semicarbazone suspended in 300 cc. of benzene is added, with vigorous stirring, a solution of 126 cc. of thionyl chloride in 360 cc. of benzene. The mixture is warmed at 50-65 for 90 minutes and then allowed to stand at room temperature over night. The solids are removed by filtration, washed with benzene and then with alcohol. After drying, the yield of N-(S-nitro-Z-furfurylidene)-3-amino-2-iminooxazolidine hydrochloride is 103 g., 95% M. P. 175-185 C.

A solution of 51 g. of N-(S-nitro-Z-furfurylidene)-3- amino-Z-iminooxazolidine hydrochloride in 1000 cc. of water is filtered to remove any insoluble material and then refluxed for one hour, crystals separating out after a short period of boiling. The mixture is filtered hot and the yellow insoluble solid washed with water and then with alcohol. After drying, the N-(5-nitro-2-furfurylidene)-3-an1ino-2-oxazolidone amounts to 21.8 g., 54.5%. M. P. 254-256" C.

C. A solution of g. of Z-hydroxyethylhydrazine in 25 cc. of alcohol is adjusted to pH 6 with alcoholic hydrogen chloride. To this is slowly added a solution of S-nitro-Z-furaldehyde in 25 cc. of alcohol, keeping the temperature at 25-30 C. This solution is treated dropwise over a period of -25 minutes, with 24.8 g. of ethyl chloroformate, the temperature being maintained at 28-32 C. After stirring at 30 C. for 70 minutes, the solution is cooled in an ice bath for 30 minutes and the solid which separates is filtered oil. The reddish crystals are recrystallized from alcohol, giving 12.4 g. of N-(S- nitro-2-furfurylidene) -N'-carbethoxy-N- (Z-hydroxyethyl) hydrazine. The latter, when dissolved in dioxane and added to a dilute solution of sodium carbonate in water gives a precipitate of N-(5-nitro-2-furfurylidene)-3- amino-Z-oxazolidone.

D. 3nitro-2-oxazolidone is reduced electrolytically, using 160 cc. of 10% sulfuric acid as the catholyte, a lead anode, a mercury pool cathode and a current density of 0.204 amp/om. for one hour at a temperature of 5-10 C. At the end of this time the aqueous solution is separated from the mercury and treated with an alcoholic solution of S-nitro-Z-furaldehyde. In this manner a yield of 43% of N-(S-nitrO-Z-furfurylidene) -3-amino- 2-oxazolidone, M. P. 256-257 C. is obtained.

4 EXAMPLE n N-(S-nitro-Z-furfurylidene)-3amin0-5-methyl-2 oxazolidone CHr-OH Using 45.0 g. of Z-hydroxypropylhydrazine (prepared by the condensation of propylene chlorohydrin with hydrazine hydrate), 74 cc. of diethyl carbonate, a solution of 1.4 g. of sodium in 16 cc. of anhydrous methanol and the procedure described in Example 1, method A (1), there is obtained g. (70.4% yield) of N-(5-nitro-2- furfurylidene) 3 amino-5-methyl-2-oxazolidone, M. P. 255-256 C.

EXAMPLE III N -(5 -nitro-2-furfurylidene) -3-amin0-4-methyl-2- oxazolidone Using 11.6 g. of 2-hydrazino-l-propanol (prepared by the reduction of ethyl a-hydrazinopropionate with lithlum aluminum hydride), 17 g. of diethyl carbonate, a solution of 1.0 g. of sodium in 10 cc. of anhydrous methanol and the procedure described in Example I, method A (1) there is obtained 11.0 g., 36%, of N-(S-nitro-Z-furfurylrdene)-3-amino-4-methyl-2-oxazolidone, M. P. 199-200 C.

EXAMPLE IV N-( 5 -nitr0-2-furfurylidene) -3-amino-5 -butyl- 2-oxazolidone O Hrc Using 4.7 g. of l-hydrazino-Z-hexauol (prepared by the condensation of 2-bromohexanol with hydrazine hydrate), 5.0 g. of diethyl carbonate, a solution of 0.1 g. of sodium in 3 cc. of anhydrous methanol and the procedure described in Example I, method A (1), there is obtained 4.6 g. (46%) of N-(S-nitrO-Z-furfurylidene)-3- amino-5-butyl-2-oxazolidone, M. P. 194".

EXAMPLE V N-(5nitr0-2-furfurylidene)-3-amino-4-butyl- 2-0xaz0lidone Using 5.5 g. of 2-hydrazino-1-hexanol (prepared by the reduction of ethyl a-hydrazinocaproate with lithium aluminum hydride), 6.5 g. of diethyl carbonate, a solution of 0.2 g. of sodium in 5.6 cc. of anhydrous methanol and the procedure described in Example I, method A (1), there is obtained 4.9 g., 42% of N-(5-nitro-2-furturylidene)-3-amino-4-butyl-2-oxazolidone, M. P. 151 C.

N (5 -nitr-2-furfurylidene) -3-amin0-4,4-dimethyl- Z-oxazolidone 1 o CC2 Ca CH3 Using 3.96 g. of 4,4-dimethyl-3-nitro-2-oxazolidone (prepared, by the nitration of 4,4-dimethyl-2-oxazolidone), and the procedure described in Example I, method D, there is obtained 2.79 g., 45%, of N-(S-nitro- Z-furfurylidene) -3-amino-v4,4-dimethyl-2-oxazolidone, M. P. 152-153" C.

EXAMPLE VIII N (5 -m' tr0-2-urfurylidene) -3-amino-4,4-dimethylmethyl-Z-oxazolidone V 0 CHr-Cfl H2011 A solution of 43 g. of sodium hydroxide in 250 g. of hydrazine hydrate (100%) is warmed to 44 and then treated with 110 g. of glycerol a-monochlorohydrin,

dropwise, over a period of 35 minutes, keeping the temperature at 85--90 C. by the rate of addition. The reaction mixture is heated on the steam bath for 30 minutes and then allowed toremain at room temperature overnight. The excess hydrazine is'removed by vacuum distillation, the residue diluted with absolute alcohol and the precipitated sodium chloride removed by filtration. The alcoholic filtrate is then refluxed with diethyl carbonate and sodium ethoxide and the procedure described in Example I, method A 1), followed to give N-(5-. nitro 2 furfurylidene) 3 amino-S-hydroxymethyl-Z- oxazolidone, M. P. 24l243 C.

EXAMPLE IX N-(5-nizro-2-furfurylidene)-3-amino-5-chloromethyl-Z-oxazolidone /O GHQ-CH A. Using g. of 5-nitro-2-furaldehyde in 50 cc. of alcohol, a solution of 10.7 g. of B-amino-S-chloromethyl- ;:0aaz9 id9ne-(Paterno .and Q ngQhn iGaZmChim. Ital. 38, 1245' eilsteimv l. 27.1w. :);and-.-the.:-pro:

cedure described in Example I, method A (1), there is" obtained a quantitative yield of;N-(5-nitro-2-furfuryli dgne)-3-aminor5;chloromethyl-2;oxazolidgne, M. P. 196- 1 7 C. v I

B. Treatment of N-(5-nitro-2-furfurylidene)-3-amino- S-hydroXymethyl-2-oxaiolidone (Example VIII) with a chloroform solution of thionyl chloride in the presence of Pyridine yields N- 5-nitro 2;furfurylideng.) 3-amino;5-

chloromethyl-2oxa2olidone, P; 196156 EXAMPLE X.

O n-o Using 50.4 g. of 3-hydrazino-2-butanol (prepared by the condensation of 2,3-epoxybutane with hydrazine hydrate), 63 g. of diethyl carbonate, a solution of 3.5 g. of sodium in 35 cc. of anhydrous methanol and the procedure described in Example I, method A (1), there is obtained 80 g. of N-(S-nitro-Z-furfurylidene)-3-amino-4,5- dimethyl-Z-oxazolidone, M. P. 143-l44 C.

What I claim is:

l. A chemical compound having chemotherapeutic activity on oral administration and represented by the for- R1 is ,a member of the group consistingof hydrogen, lower alkyl, hydroxy (lower) alkyl and halogeno (lower) alkyl R2 is a member of the group consisting of hydrogen,

lower alkyl, hydroxy (lower) alkyl and halogeno (lower) alkyl R3 is a member of the group consisting of hydrogen, lower alkyl, hydroxy (lower) alkyl and halogeno (lower) alkyl R4 is a member of the group consisting of hydrogen, lower alkyl, hydroxy (lower) alkyl and halogeno- (lower) alkyl 2. N (5-nitro-2-furfurylidene) 3-amino-2-oxazolidone represented by the formula:

3. N (5 nitro 2-furfurylidene)-3-amino-5-hydroxy methyl-Z-oxazolidone represented by the formula: v

7 8 4. N (5-nitro-2-furfurylidene)-3-amino-5-chlorometh- 6. N (S-nitro 2-furfurylidene)-3-amino-5-methyl-2- yl-Z-oxazolidone represented by the formula: oxazolidone represented by the formula:

Hs-Cfi cm-c H201 1 H; 5 N 'y y References Cited in the file of this patent 2-oxazolidone represented by the formula: UNITED STATES PATENTS 2,484,503 Harmer Oct. 11, 1949 2519,001 Spra ue Aug. 15 1950 N a z: y 0 CH N N 15 2,553,494 Anish May 15, 1951 0 2,610,181 Hayes Sept. 9, 1952 H-O H AH; 

1. A CHEMICAL COMPOUND HAVING CHEMOTHERAPEUTIC ACTIVITY AN ORAL ADMINISTRATION AND REPRESENTED BY THE FORMULA: 